Abstract

Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to deficient conversion of phenylalanine (Phe) to tyrosine and accumulation of toxic levels of Phe. A Phe-restricted diet is essential to reduce blood Phe levels and prevent long-term neurological impairment and other adverse sequelae. This diet is commenced within the first few weeks of life and current recommendations favor lifelong diet therapy. The observation of clinically significant reductions in blood Phe levels in a subset of patients with PKU following oral administration of 6R-tetrahydrobiopterin dihydrochloride (BH(4)), a cofactor of PAH, raises the prospect of oral pharmacotherapy for PKU. An orally active formulation of BH(4) (sapropterin dihydrochloride; Kuvan is now commercially available. Clinical studies suggest that treatment with sapropterin provides better Phe control and increases dietary Phe tolerance, allowing significant relaxation, or even discontinuation, of dietary Phe restriction. Firstly, patients who may respond to this treatment need to be identified. We propose an initial 48-h loading test, followed by a 1-4-week trial of sapropterin and subsequent adjustment of the sapropterin dosage and dietary Phe intake to optimize blood Phe control. Overall, sapropterin represents a major advance in the management of PKU.